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Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, ConnecticutVA Connecticut Healthcare System, West Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, ConnecticutDepartment of Vascular Surgery, University Hospital of Nice, Nice, France
Yale University Vascular Biology and Therapeutics Program, New Haven, ConnecticutDepartment of Surgery, Yale University School of Medicine, New Haven, ConnecticutVA Connecticut Healthcare System, West Haven, Connecticut
Veins are exposed to the arterial environment during two common surgical procedures, creation of vein grafts and arteriovenous fistulae (AVF). In both cases, veins adapt to the arterial environment that is characterized by different hemodynamic conditions and increased oxygen tension compared with the venous environment. Successful venous adaptation to the arterial environment is critical for long-term success of the vein graft or AVF and, in both cases, is generally characterized by venous dilation and wall thickening. However, AVF are exposed to a high flow, high shear stress, low-pressure arterial environment and adapt mainly via outward dilation with less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high-pressure arterial environment and adapt mainly via increased wall thickening with less outward dilation. We review the data that describe these differences, as well as the underlying molecular mechanisms that mediate these processes. Despite extensive research, there are few differences in the molecular pathways that regulate cell proliferation and migration or matrix synthesis, secretion, or degradation currently identified between vein graft adaptation and AVF maturation that account for the different types of venous adaptation to arterial environments.
Vascular surgeons expose veins to the arterial environment during two common procedures, creation of vein grafts and arteriovenous fistulae (AVF). Adaptation of veins to the arterial environment, including the different hemodynamic conditions and increased oxygen tension, is characterized by venous wall dilation and thickening as an integration of the underlying processes of cellular migration and proliferation, as well as extracellular matrix deposition and remodeling. Successful venous adaptation is critical for long-term success of the vein graft or AVF, whereas unsuccessful adaptation, either insufficient or exuberant, may be a source of conduit failure that leads to patient morbidity and even mortality. Although our understanding of venous adaptation has substantially increased, this knowledge has not translated into successful therapy, and, accordingly, the failure rates of both vein grafts and AVF remain high, resulting in both patient suffering and significant health care expenditure [
AVF are the current optimal and preferred conduit for vascular access for hemodialysis. Compared with arteriovenous grafts and central venous catheters, AVF have the longest patency with fewest complications [
Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.
]. Despite their superiority among dialysis access choices, AVF still exhibit relatively high failure rates, as high as 60% failing to mature adequately to support hemodialysis in some reports [
Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy.
]. Coronary artery vein grafts have higher patency rates, with 1-y patency rates of approximately 75%–90%, and 5- to 10-y patency rates >75% that decrease to 50% at ≥15 y [
Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up.
Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years.
The surgical formation of a vein graft or an AVF exposes the vein to the arterial environment of high blood flow and pressure that are typically considered injurious and that stimulate venous adaptation to the new environment [
]. This review compares both physiological and molecular adaptation of veins (“venous remodeling”), as either vein grafts (“vein graft adaptation”) or AVF (“AVF maturation”), to this different environment, using literature specific to venous adaptation and not based on arterial data.
2. Surgical procedure
Several aspects of the surgical procedure are noteworthy and likely to affect venous remodeling. Vein grafts can be performed either in reversed, nonreversed, or in situ fashion, generally at the discretion of the surgeon. Reversed vein grafts create a flow environment in which the endothelial cells remain aligned to the direction of flow and the valves remain in their normal alignment, allowing antegrade flow with minimal resistance or disturbance. Nonreversed vein grafts are prepared similarly but require valve destruction, creating flow disturbance and even turbulence near the valve remnants; the endothelial cells remain aligned to the direction of flow but the flow direction is 180° reversed compared with the native venous flow. In situ vein grafts similarly require valve destruction and have reversed flow on the endothelial cells, but the veins are not removed from the native tissue bed, leaving the venous adventitia, as well as the vasa vasorum and nervous innervation, intact. Vein grafts, both reversed and nonreversed, require extensive handling and irrigation, resulting in spasm as well as endothelial damage and inflammation [
]. During coronary artery bypass, veins may be exposed to the colder environment of the bypass flow circuit and cardioplegia.
Similarly, AVF may be created directly or transposed from a deeper bed, although transposition in reversed configuration with valve destruction is distinctly less common. The AVF procedure is usually performed with less mobilization and surgical manipulation of the vein compared with vein grafts, resulting in AVF being performed more quickly and with less trauma, ischemia, and endothelial injury compared with vein grafts.
The systemic environment created by the comorbid conditions of the patient is often quite different between vein grafts and AVF. Vein grafts are typically created in patients with cardiovascular disease that is similarly frequently present in patients needing AVF. However, patients with AVF have advanced renal disease and uremia that is not present in many patients requiring vein grafts. Uremia is an independent factor that predisposes the AVF to failure to mature [
]. AVF are also cannulated for dialysis multiple times a week, unlike vein grafts that reside in atraumatic environments.
3. Flow and pressure
The minimum blood flow for hemodialysis in the United States is generally 350–450 mL/min, and to prevent venous collapse, the flow rate should exceed this minimum rate by at least 100 mL/min [
]. High flow rates correlate with successful access maturation, with 84% of fistulae with flows >500 mL/min eventually being adequate for dialysis, whereas only 43% of fistulas with flows <500 mL/min becoming adequate [
]. The National Kidney Foundation Clinical Practice Guidelines recommend a flow rate of 400–500 mL/min as a minimal threshold for re-evaluation of a fistula [
]. In Europe and Japan, however, hemodialysis is currently performed with lower flow rates but with longer sessions compared with those performed in the United States [
]. Studies evaluating successful radial-cephalic AVF reveal normal flow rates averaging between 600 and1000 mL/min, with many individual AVF exposed to even higher peak flows, and this magnitude of flow increases substantially in the larger diameter brachial-cephalic AVF (Table 2). Dixon et al. [
] reported that 90% of forearm AVF have flow between 500 and 2000 mL/min, whereas 90% of upper arm AVF have flow between 500 and 3000 mL/min. Corpataux et al. reported that shear stress increases from 5–10 dyne/cm2 to 24.5 dyne/cm2 after 1 wk, which then normalizes to 10.4 dyne/cm2 >3 mo [
]. The substantially increased magnitude of blood flow in the AVF, typically much higher compared with arterial flow, we call “supra-arterial” magnitudes of flow (Table 1). With these high magnitudes of flow in the AVF, the character of the flow may be disturbed, for example, nonlaminar and highly disordered, even turbulent [
Early (8–12 d postoperatively): To LAD: 79 ± 39 mL/min To Right Circumflex: 65 ± 17 mL/min To Left Circumflex: 68 ± 25 mL/min Late (average 2.5 y): To LAD: 67 ± 31 mL/min To Right Circumflex: 42 ± 17 mL/min To Left Circumflex: 60 ± 24 mL/min
The blood flow within vein grafts varies depending on several variables, including type of procedure, length and diameter of conduit, and the amount of resistance in the runoff bed distal to the vein graft. Accordingly, average flow rates for lower extremity bypasses typically vary from <100 to >300 mL/min, whereas average flow rates for coronary artery bypass are often <100 mL/min (Table 2). Flow rates over time are extremely difficult to assess, as the presence of a failing graft, even subclinically, as well as advancing proximal and/or distal disease, are significant confounding variables that usually precipitate intervention. Nevertheless, most studies show that vein grafts are exposed to flows of the arterial circulation that are typically much lower magnitude than to which AVF are exposed.
In lower extremity vein grafts, average intraoperative shear stress was measured to be 23–27 dyne/cm2, which decreases by 1 y to 12 dyne/cm2 [
] showed that smaller diameter vein grafts are associated with much higher values of shear stress, with these values normalizing to 6–10 dyne/cm2 by 12 mo. Coronary vein grafts generally dilate little and have lower magnitudes of flow, with shear stress values reported to be ≤5 dyne/cm2 [
] measured the cephalic vein pressure to be 49 ± 19/24.5 ± 6 mm Hg (systolic/diastolic) immediately after radial-cephalic AVF creation, and this did not increase 13 mo later. Animal studies are also generally consistent with this small increase in pressure [
]. In toto, extensive examination shows that vein grafts are exposed to arterial magnitudes of pressure and flow, whereas AVF are exposed to supra-arterial magnitudes of flow at pressures typically much lower than arterial systolic pressure (Table 1).
4. Outward remodeling
Adaptation of the vein to the increased flow and shear stress of the arterial environment requires dilation by outward remodeling of the venous wall, described by Poiseuille's law, whereas increases in pressure and tensile stress require wall thickening, described by Laplace's law. These changes are thought to be mediated by the venous endothelium that senses hemodynamic forces and integrates these forces to allow successful adaptation without loss of luminal area and vessel patency [
]. Several studies examining venous dilation in AVF reported mean diameter increases from 2.3–3.2 to 5.8–6.6 mm, 3 mo after fistula creation. These values reflect a 45%–86% increase within the first month and an increase of up to 179% after 3 mo, correspond to an average cross-sectional area of approximately 10–12 mm2, and were associated with normalization of the shear stress [
Lower extremity vein grafts are associated with average dilation of approximately 20%–30% during the first few months after surgery, with minimal dilation afterward [
] reported that at 1 y postoperatively, initially smaller diameter vein grafts tended to dilate 20%–25%, whereas initially larger diameter vein grafts tended to constrict 10%–15%, achieving similar final diameters. Vein grafts in the coronary circulation may also show flow-mediated diameter remodeling, although they frequently exhibit a small amount of inward remodeling, consistent with their lower flow [
Lumen loss in the first year in saphenous vein grafts is predominantly a result of negative remodeling of the whole vessel rather than a result of changes in wall thickness.
]. Thus, both vein grafts and AVF remodel their diameters, usually by dilation, depending on the magnitudes of flow in the new environment, normalizing the shear stress sensed by the venous endothelium.
5. Wall thickening
Wall thickening is the adaptation of the vessel wall to increased pressure; thickening has been studied extensively in several models of vascular injury and adaptation, especially in the arterial angioplasty and hypertension models. These models have shown that this process involves expansion of all the layers of the vessel via both extracellular matrix (ECM) deposition, as well as via cell proliferation and migration [
]. Several types of cells are involved in wall thickening, including smooth muscle cells, adventitial fibroblasts, and bone marrow–derived progenitor cells. In addition to proliferation, smooth muscle cells may migrate from the medial to the intimal layer and differentiate from a contractile to synthetic phenotype; fibroblasts may similarly differentiate into myofibroblasts [
Early remodeling of saphenous vein grafts: proliferation, migration and apoptosis of adventitial and medial cells occur simultaneously with changes in graft diameter and blood flow.
Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat.
]. Bone marrow–derived progenitor cells are capable of differentiation into both endothelial and smooth muscle cells within both AVF and vein grafts, although whether this occurs in humans is not clear [
] reported increased wall thickness during human vein graft adaptation, from 0.47 ± 0.03 to 0.61 ± 0.004 mm, during the first 6 mo after implantation. Using intravascular ultrasound, Higuchi et al. [
] reported increased wall cross-sectional area in AVF although the small increase in the AVF is likely due to the lower pressure in the AVF compared with the coronary vein graft.
6. Venous remodeling integrates outward remodeling and wall thickening
AVF are exposed to a high flow, high shear stress, low-pressure arterial environment and adapt mainly via outward dilation and less intimal thickening. Vein grafts are exposed to a moderate flow, moderate shear stress, high-pressure arterial environment and adapt mainly via increased wall thickening with less outward dilation (Fig. 1). Schwartz et al. [
] confirmed this behavior using a rabbit model, showing that AVF are exposed to higher flow than vein grafts (AVF: 82 ± 17 mL/min; vein grafts: 16 ± 4 mL/min) as well as increased shear stress (AVF: 71 ± 50 dyne/cm2; VG: 0.96 ± 0.38 dyne/cm2) that was associated with increased dilation (AVF: 194%; VG: no change); vein grafts are exposed to higher pressure (VG: 62 ± 3 mmHg; AVF: 6 ± 2 mmHg) and had increased myointimal area (VG: 4.72 ± 0.83 mm2; AVF: 1.9 ± 0.55 mm2). Interestingly, Zilla et al. [
] recently showed in a nonhuman primate model that vein grafts in the coronary circulation had lower mean velocity and shear stress, and lumen constriction and increased intimal thickening, compared with peripheral vein grafts that dilate.
Fig. 1Schema of vein graft adaptation and AVF maturation. AVF adapt largely through outward remodeling in response to supra-arterial flow, whereas vein grafts adapt largely through intimal/medial thickening in response to arterial pressure. + = positive; +++ = significantly positive.
The developmental origin of vascular endothelial cells and smooth muscle cells is different, with Ephrin-B2 being a determinant of arteries and Eph-B4, a determinant of veins in the developing embryo; these determinants persist as markers of identity on adult vessels [
]. Vein graft adaptation is characterized by loss of Eph-B4 expression, for example, loss of venous identity, but Ephrin-B2 is not expressed, for example, arterial identity is not gained [
]. However, similar characterization of the changes that occur during AVF maturation is not yet available. Downstream signaling in the Ephrin-Eph pathway may mediate many effects of venous remodeling, but the significance of this pathway as a potential source of therapeutic manipulation is not yet known. However, because Eph signaling is the upstream of the E2F pathway, modulation of the Eph pathway may provide therapeutic benefit, unlike the disappointing failure of the PREVENT trials [
The venous endothelium releases mitogens and chemotactic agents, regulators of extracellular matrix remodeling, and vasoactive signals that regulate wall dilation to allow vessel adaptation to flow, shear stress, pressure, and tension (Fig. 2) [
]. Endothelial injury and denudation disrupt endothelial signaling leading to impaired adaptation. Flow-related endothelial denudation can occur within hours of AVF creation, and chronic kidney disease may delay re-endothelialization; denudation leads to barrier dysfunction, exposure of subendothelial collagen, thrombus formation, and inflammatory cell extravasation into the vein wall [
]. Both the stress of the arterial environment and the surgical injury likely contribute to endothelial loss and dysfunction. The endothelium is regenerated 2 wk after both vein graft implantation and AVF creation, although endothelial proliferation continues for several weeks afterward [
In endothelial cells, nitric oxide (NO) is produced by endothelial nitric oxide synthase (eNOS) and is a potent vasodilator and signaling molecule with anti-inflammatory and anti-platelet properties [
]. eNOS may contribute to adaptive vein wall remodeling both through its anti-inflammatory and anti-thrombotic properties and through its anti-proliferative properties [
]. Both eNOS and inducible nitric oxide synthase are upregulated in the AVF and may mediate adaptation; inhibition of eNOS results in increased monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-8, leading to neointimal hyperplasia [
Intraluminal gene transfer of endothelial cell-nitric oxide synthase suppresses intimal hyperplasia of vein grafts in cholesterol-fed rabbit: a limited biological effect as a result of the loss of medial smooth muscle cells.
Endothelin-1 (ET-1) is an inflammatory mediator of vasoconstriction and endothelial proliferation. ET-1 expression is upregulated in the venous wall and within areas of neointimal hyperplasia in AVF and in the plasma of patients with chronic renal failure and hemodialysis. ET-1 may mediate wall thickening in response to localized hemodynamic forces [
]. Similarly in vein grafts, high densities of ET-1 receptors are present within subintimal regions that coincide with areas of proliferating cells. In a pig vein graft model, treatment with an ET-1 receptor antagonist resulted in decreased cell proliferation, decreased intimal and medial vein graft thickening, and increased luminal dilation [
The endothelin 1A receptor antagonist BSF 302146 is a potent inhibitor of neointimal and medial thickening in porcine saphenous vein-carotid artery interposition grafts.
The opposing roles played by ET-1 and NOS are balanced by the venous endothelium during vein graft adaptation; however, arterial stress-induced endothelial injury and denudation disrupts this balance and likely is a mechanism of impaired venous adaptation. This pathway may be fruitful for consideration of modulation in future clinical studies. However, differences between arterial and venous ET-1 function suggest that results derived from arterial models may need to be interpreted cautiously in the context of venous remodeling [
Numerous inflammatory mediators are present during venous remodeling. In an AVF, inflammatory cells accumulate rapidly, with additional accumulation in segments that thrombose [
]. IL-6, IL-8, MCP-1, and plasminogen activator inhibitor-1 (PAI-1) expressions are upregulated in the AVF, and these mediators are associated with fistula failure [
]. IL-6 and tumor necrosis factor-α are more highly expressed in thrombosed AVF, and both C-reactive protein (CRP) and fibrinogen are associated with AVF failure [
The anti-inflammatory molecule heme oxygenase-1 (HO-1), an inducible stress protein involved in heme metabolism, regulates ECM deposition, endothelial proliferation, oxidative stress, and smooth muscle proliferation. HO-1 expression is upregulated within AVF and reduced HO-1 activity is associated with AVF failure [
Inflammatory cells such as macrophages and granulocytes are recruited to vein grafts rapidly after implantation and are associated with expression of both proinflammatory and anti-inflammatory mediators; increased expression of inflammatory mediators may result in negative wall remodeling and intimal hyperplasia [
]. Interestingly, there is significantly higher induction of the proinflammatory IL-1β and less induction of the anti-inflammatory IL-10 within low flow vein grafts that correlates with increased intimal hyperplasia [
]. Elevated high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation, is associated with impaired positive remodeling, increased wall stiffness, suggesting an increased risk of failure in vein grafts [
]. Similar to the data reported for AVF, HO-1 is also protective against vein graft failure, as vein grafts derived from HO-1 knockout mice demonstrate enhanced neointima compared with veins from wild-type mice [
Oxidative stress and injury stimulates synthesis and secretion of reactive oxygen species (ROS) that in turn regulate numerous signaling pathways, regulating diverse processes such as smooth muscle cell migration and proliferation, and activate latent MMP, potentially mediating many aspects of venous remodeling [
]. In the venous limb of the AVF markers and products of oxidative stress are elevated in neointimal lesions, often colocalizing with the cytokines of growth and proliferation [
]. AVF demonstrate increased superoxide and decreased superoxide dismutase coordinately with induction of HO-1; addition of a superoxide scavenger decreases venous neointimal thickening and calcification within the AVF [
With increased surgical manipulation, including removal from the surrounding tissues and disruption of vasa vasorum, vein grafts are associated with oxidative stress as well as ischemia-reperfusion injury that lead to generation of ROS [
]. Superoxide is reciprocally related to NO function, as decreased intimal hyperplasia is associated with decreased superoxide production and increased NO-mediated vein graft relaxation [
Celiprolol reduces the intimal thickening of autogenous vein grafts via an enhancement of nitric oxide function through an inhibition of superoxide production.
Venous adaptation depends on coordinate synthesis, secretion, and degradation of ECM. The MMP family regulate ECM remodeling and allow cell migration through degradation of collagen and elastin and is stimulated by a variety of factors present during vein graft adaptation including flow, stretch, mechanical injury, inflammation, and oxidative stress [
]. In AVF, MMP-2 and MMP-9 expressions are upregulated, and a high serum ratio of MMP-2 to tissue inhibitor of metalloproteinases (TIMP) predicts AVF maturation [
]. Decreased expressions of MMP-1, MMP-3, and MMP-9 have been linked to increased AVF failure and stenosis that may be due to accumulation of ECM and impaired wall remodeling [
Increased expression of HIF-1alpha, VEGF-A and its receptors, MMP-2, TIMP-1, and ADAMTS-1 at the venous stenosis of arteriovenous fistula in a mouse model with renal insufficiency.
]. Other elastases such as cathepsin S and cathepsin K are also upregulated in the AVF and may be associated with degradation of the internal elastic lamina [
]. Both MMP-2 and MMP-9 expressions are upregulated in the early developing neointima of vein grafts but decline to baseline between 3 and 6 mo, suggesting their role in early remodeling and cell migration [
]. Interestingly, surgical preparation of vein grafts, including harvest, adventitial removal, distention, exposure to cold temperature, and so forth, activates MMP-2 and MMP-9 and coincides with partial endothelial denudation [
]. Elastase is also upregulated in vein grafts, and expression of an elastase inhibitor, elafin, protects against vein graft neointimal hyperplasia and inflammation within the venous wall [
Matrix degradation is regulated by MMP, whereas matrix deposition is regulated by transforming growth factor-β (TGF-β) that is produced by a variety of cell types, including endothelial, smooth muscle, and inflammatory cells, potentially contributing significantly to intimal and medial thickening [
]. TGF-β is upregulated at both early and later time points after AVF formation, depending on the model, and this expression correlates with ECM accumulation; TGF-β is also expressed within stenotic AVF and correlates with areas of ECM deposition [
Numerous growth factors and cytokines play a role during venous adaptation, both through pathways that control ECM synthesis, secretion, and degradation and through the control of cell proliferation and migration. For example, insulin-like growth factor-1 (IGF-1) induces ECM synthesis, smooth muscle proliferation and migration, and inhibits apoptosis in AVF [
]. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) also play significant roles in stimulating cell proliferation and migration [
]. Vascular endothelial growth factor (VEGF) plays several roles in vascular remodeling, including stimulation of endothelial proliferation and differentiation, modulation of smooth muscle cell proliferation and migration, angiogenesis, and modulation of the inflammatory response [
]. Interestingly, VEGF may play an inhibitory role in AVF adaptation because inhibition of VEGF-A is associated with increased lumen area and decreased inward remodeling [
]. IGF-1 receptor expression is upregulated by mechanical stretch and deletion of the IGF-1 receptor leads to diminished neointimal hyperplasia in vein grafts [
]. VEGF expression is upregulated during vein graft implantation and is a negative regulator of intimal hyperplasia; inhibition of VEGF activity increases thickness of the vein graft intima-media [
MCP-1 regulates chemotaxis, endothelial activation, and stimulation of smooth muscle proliferation and migration, and plasma MCP-1 levels are increased in patients with kidney disease. [
]. MCP-1 is increased in AVF and reduced MCP-1 activity is associated with increased AVF patency, increased luminal area and decreased wall thickness [
Selectins facilitate leukocyte adhesion. P-selectin is present on endothelial cells and platelets, and E-selectin is present on endothelial cells; intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) facilitate additional binding and migration [
]. β-catenin and c-Myc expressions are increased 1 wk after AVF creation, correlating with decreased N-cadherin and associated with smooth muscle cell proliferation [
]. In vein grafts, ICAM-1 expression is increased soon after implantation, and vein grafts derived from ICAM knockout mice have fewer adherent macrophages and 30%–50% less neointimal hyperplasia [
Despite the ability of vein grafts and AVF to remodel and adapt successfully to the arterial environment, vein grafts and AVF still exhibit significant rates of failure. AVF show two distinct phases of failure; AVF failure can occur early due to lack of sufficient maturation, as well as failure later, after successful maturation, due to neointimal hyperplasia that may result in stenosis or thrombosis. Vein grafts show similar patterns of early and later failure. We believe that despite somewhat different mechanisms of vein graft and AVF remodeling to the arterial environment, failure of successful remodeling leads to the early phase of clinical failure in both cases; similarly, later failure is generally associated with progression of disease in both cases as well. However, it is still not known whether the mechanisms that regulate successful venous remodeling become dysregulated and lead to later conduit failure. Therapeutic approaches to prevent failure include both cell-based therapies and gene therapy targeting many of the molecular pathways addressed in this article. Although a detailed review of these approaches is beyond the scope of this article, several excellent reviews have addressed this topic in detail [
The molecular mechanisms leading to cell proliferation and migration, and ECM synthesis, secretion, and degradation, are remarkably similar during vein graft and AVF adaptation to the arterial environment. Despite differences in vein graft adaptation, characterized mainly by wall thickening, and AVF maturation, characterized mainly by outward remodeling, the lack of identifiable molecular differences between these two processes remains a gap in our understanding of venous remodeling. Research directed toward understanding the effects of different hemodynamic and other environmental forces on veins may identify molecular differences between vein graft adaptation and AVF maturation and may depend on understanding the fundamental biological differences between responses of arteries and veins to these stimuli. Additional areas of research include regulation of apoptosis, endothelial phenotype, and the role of endothelial progenitor cells in venous remodeling.
Acknowledgment
This work was supported by the National Institutes of Health R01-HL095498 (A.D.) and TL1-RR024137 grants (D.Y.L.), the Yale Department of Surgery Ohse award (K.Y. and C.D.P.), the Yale University Medical Student Research Fellowship (E.Y.C.), the Society of Vascular Surgery Student Research Fellowship (E.Y.C.), the Doris Duke Foundation Clinical Fellowship (D.J.W.), as well as with the resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT (K.Y. and A.D.).
Disclosure
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.
Vascular access survival and incidence of revisions: a comparison of prosthetic grafts, simple autogenous fistulas, and venous transposition fistulas from the United States Renal Data System Dialysis Morbidity and Mortality Study.
Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: an intention-to-treat analysis of amputation-free and overall survival in patients randomized to a bypass surgery-first or a balloon angioplasty-first revascularization strategy.
Internal mammary artery versus saphenous vein graft to the left anterior descending coronary artery: prospective randomized study with 10-year follow-up.
Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years.
Lumen loss in the first year in saphenous vein grafts is predominantly a result of negative remodeling of the whole vessel rather than a result of changes in wall thickness.
Early remodeling of saphenous vein grafts: proliferation, migration and apoptosis of adventitial and medial cells occur simultaneously with changes in graft diameter and blood flow.
Apoptosis, cell proliferation and modulation of cyclin-dependent kinase inhibitor p21(cip1) in vascular remodelling during vein arterialization in the rat.
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